Pozzi Ambra, Jarad George, Moeckel Gilbert W, Coffa Sergio, Zhang Xi, Gewin Leslie, Eremina Vera, Hudson Billy G, Borza Dorin-Bogdan, Harris Raymond C, Holzman Lawrence B, Phillips Carrie L, Fassler Reinhard, Quaggin Susan E, Miner Jeffrey H, Zent Roy
Department of Medicine, Veterans Affairs Hospital, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Dev Biol. 2008 Apr 15;316(2):288-301. doi: 10.1016/j.ydbio.2008.01.022. Epub 2008 Jan 31.
Integrins are transmembrane heteromeric receptors that mediate interactions between cells and extracellular matrix (ECM). beta1, the most abundantly expressed integrin subunit, binds at least 12 alpha subunits. beta1 containing integrins are highly expressed in the glomerulus of the kidney; however their role in glomerular morphogenesis and maintenance of glomerular filtration barrier integrity is poorly understood. To study these questions we selectively deleted beta1 integrin in the podocyte by crossing beta1(flox/flox) mice with podocyte specific podocin-cre mice (pod-Cre), which express cre at the time of glomerular capillary formation. We demonstrate that podocyte abnormalities are visualized during glomerulogenesis of the pod-Cre;beta1(flox/flox) mice and proteinuria is present at birth, despite a grossly normal glomerular basement membrane. Following the advent of glomerular filtration there is progressive podocyte loss and the mice develop capillary loop and mesangium degeneration with little evidence of glomerulosclerosis. By 3 weeks of age the mice develop severe end stage renal failure characterized by both tubulointerstitial and glomerular pathology. Thus, expression of beta1 containing integrins by the podocyte is critical for maintaining the structural integrity of the glomerulus.
整合素是跨膜异源二聚体受体，介导细胞与细胞外基质（ECM）之间的相互作用。β1是表达最丰富的整合素亚基，可与至少12种α亚基结合。含β1的整合素在肾脏肾小球中高度表达；然而，它们在肾小球形态发生和维持肾小球滤过屏障完整性中的作用却知之甚少。为了研究这些问题，我们通过将β1（flox/flox）小鼠与足细胞特异性足动蛋白-cre小鼠（pod-Cre）杂交，在足细胞中选择性删除β1整合素，后者在肾小球毛细血管形成时表达cre。我们证明，在pod-Cre;β1（flox/flox）小鼠的肾小球发生过程中可观察到足细胞异常，并且尽管肾小球基底膜大体正常，但出生时就存在蛋白尿。随着肾小球滤过的出现，足细胞逐渐丢失，小鼠出现毛细血管袢和系膜变性，几乎没有肾小球硬化的迹象。到3周龄时，小鼠发展为严重的终末期肾衰竭，其特征为肾小管间质和肾小球病变。因此，足细胞表达含β1的整合素对于维持肾小球的结构完整性至关重要。
